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For clinicians tasked with treating patients with prostate cancer, disease visualization has traditionally consisted of imprecise techniques such as MRI. However, a new artificial intelligence (AI)-based approach being developed by Avenda Health is poised to potentially revolutionize the treatment landscape in the field.

The iQuest system is a patient management software that uses AI and deep learning technology to map a patient’s prostate cancer, aiding clinicians in identifying the extent of a patient’s disease. It is meant to be paired with their proprietary FocalPoint laser ablation system, which is designed to treat localized prostate cancer under local anesthesia. Avenda believes that this dual approach can lead to improved outcomes for patients with prostate cancer with preserved quality of life.

“Prostate cancer is unique, as it is one of the only solid cancers we cannot image very well,” Brittany Berry-Pusey, PhD, cofounder and chief operating officer of Avenda Health in Los Angeles, California, said in an interview with 

. “On an MRI alone, radiologists can identify hot spots, but they cannot tell you exactly where the cancer is. The only way we can truly diagnose is through biopsies. [With the iQuest system], we have taken all these data—we use the MRI images, biopsy information, and pathology reports—to create a cancer probability map. We [calculate] voxel-level probability of clinically significant prostate cancer, and we help the physician identify cancer margins.”

The FocalPoint laser ablation system, also known as the Orion System, is designed to deliver targeted treatment via laser ablation and preserve the patient’s urinary and sexual function as much as possible. Using ultrasound guidance, a laser needle and sensor are inserted into the target tissue, and the needle is then heated, leading to coagulation necrosis. The system also allows the clinician to monitor tissue temperature and treatment progress in real time.

On May 11, 2021, the FDA granted breakthrough device designation to Avenda Health for a lumpectomy product, which was eventually developed into the FocalPoint system. The designation was partially based on the results of a phase 1 trial (NCT04305925) of 10 patients, showing the system was safe and resulted in no decline in urinary or sexual function.

More recently, in August 2022, the FDA awarded an investigational device exemption to the FocalPoint system powered by iQuest.

 “It is unfortunate that 50% of men with prostate cancer will have urinary or sexual dysfunction caused by their therapy,” Berry-Pusey said. “We have better solutions for these patients and [can] treat their prostate cancer [and] preserve their quality of life. That is the promise of iQuest and FocalPoint.”

iQuest Guides FocalPoint to Impressive Results

In May 2022, Priester et al presented 2 abstracts on behalf of Avenda Health at the Engineering and Urology Society 35th Annual Meeting in New Orleans, Louisiana, that demonstrated the efficacy of the iQuest system and that of the FocalPoint technique in patients with prostate cancer.

The first abstract outlined the development and validation of the iQuest system. The machine learning algorithm estimates voxel-level risk of clinically significant prostate cancer and produces a 3-dimensional lesion heat map. Investigators also used whole-mount prostatectomy data to develop a novel metric, the Marks Confidence Score, that correlates the lesion heat maps with the probability of encapsulating all clinically significant prostate cancers. This ultimately aids clinicians in identifying favorable candidates for focal therapy and estimating the efficacy of proposed treatment margins.

The model was developed using data from 875 patients from multiple institutions. Study authors input T2-weighted MRI data, surface models of the prostate, Prostate Imaging Reporting & Data System regions of interest, and tracked biopsy cores. The algorithm created lesion heat maps for 50 whole-mount prostatectomy cases, and a second set of 50 whole-mount prostatectomy findings from an outside institution were used for comparison to validate the Marks Confidence Scores.

For each case the area under the Marks Confidence curve was calculated by plotting Marks Confidence Score vs margin volume. The study authors hypothesized that patients with a high area under the Marks Confidence curve (≥ 0.6) would be favorable candidates for focal therapy.

Investigators found no significant differences between the observed clinically significant prostate cancer encapsulation rate compared with the rate predicted by the Marks Confidence Score (

 = .099). The median error rate was 2% (IQR, 0%-6%). The average margin volume for clinically significant prostate cancer encapsulation was lower for patients deemed as favorable candidates for focal therapy (n = 24) compared with those who were unfavorable candidates (n = 26), at 31% and 52%, respectively (

In the second abstract, Priester et al leveraged the iQuest system to generate treatment margins and compared the margins with those produced by the standard-of-care methodology. The standard-of-care techniques consisted of hemi-gland margins or a 10-mm isotropic expansion of MRI-visible regions of interest.

The machine learning model margins improved sensitivity for clinically significant prostate cancer-bearing voxels (96.9%) compared with the hemi-gland margins (94.1%; 

 < .001). Additionally, the margins generated by the algorithm surpassed hemi-gland margins in terms of the per-patient rate of complete clinically significant prostate cancer encapsulation, at 80% vs 56%, respectively (

 = .01). The iQuest system also improved clinically significant prostate cancer mean sensitivity and encapsulation rates compared with the margins calculated using 10-mm region of interest; however, the difference was not statistically significant (

“If we have the end goal of treating just the cancerous lesions [and] leaving the healthy prostate intact, which is the goal of focal therapy in general, you need to know where the cancer is,” Berry-Pusey said. “iQuest helps with identifying where the cancer truly is. [Then], now that we know where the cancer is, we can treat just the cancerous lesions [with FocalPoint] leaving the rest of the healthy prostate intact.” Additionally, Priester et al presented another related study at the meeting that highlighted an automated method that could be used for ablation site placement for a variety of treatment modalities, including the FocalPoint system. Study authors wrote an algorithm in Python that was designed to be a modality-agnostic method for ablation site selection.

The algorithm required the locations of the interstitial treatment applicators to be inputted as points of origin. Three-dimensional surfaces for the prostate, region of interest, margin intended for treatment, and ablation volume were also required.

Investigators tested the algorithm on 11 unilateral and 6 bilateral margins collected from 11 patients who had previously undergone focal treatment for prostate cancer. They measured margin encapsulation of the ablation volume aggregate for 18 versions of ablation volume size and shape. Size was measured in transverse diameters (12 mm, 18 mm, and 26 mm) and the tested geometry consisted of spheres, ellipses, capsules, cubes, prims, and custom shapes for a total of 306 unique instances that were evaluated.

Findings from the study showed that the algorithm took an average of 2.25 seconds (range, 0.4-6.5) to run to completion and placed an average of 11 ablation volumes (range, 1-41). The highest rate of mean coverage occurred in prism-shaped ablation volumes (99.1%), followed by cubes (98.8%), capsules (94.4%), custom shapes (91.6%), spheres (90.0%), and ellipses (89.1%). Mean margin coverage achieved with the algorithm was significantly higher compared with manual planning, 94% vs 87%, respectively (

 = .005). Study authors concluded that this methodology could potentially be used to simplify the planning process for focal treatment of prostate cancer through the automation of ablation site placement.

The investigational device exemption from the FDA has paved the way for the iQuest and the FocalPoint systems to be used in tandem in a randomized, controlled clinical trial of patients with prostate cancer. The trial will compare the approach with the standard of care. Berry-Pusey noted that the trial will tackle the current primary limitation of the iQuest plus FocalPoint ablation approach, which is a lack of understanding of the exact superiority of the technology compared with current techniques in a controlled setting.

The upcoming trial was designed based on outcomes from workshops conducted by the FDA to determine the best approach to conduct a clinical trial in the particular field of prostate cancer, according to Berry-Pusey. The primary outcome measure will be progression-free survival.

“We really are excited for this trial—we think that this will be the marquee study in this field,” Berry-Pusey said. “[We believe that] iQuest and FocalPoint [are] the future of prostate cancer care. We are excited to get the data and the support of our clinical partners as we improve treatment options for men with prostate cancer.”

Berry-Pusey envisions the iQuest system moving upstream in the care pathway and being used more extensively as a patient management software. She also noted that the software will be able to help clinicians with risk stratification for each individual patient and aid in identifying more personalized treatment plans.

“The personalization that iQuest creates for each patient will help patients and physicians make better decisions about their care in the future,” she said.

Avenda Health receives FDA investigational device exemption for AI-enabled prostate cancer therapy. News release. Avenda Health. August 9, 2022. Accessed August 19, 2022. prn.to/3SWiVvr

A revolution in prostate cancer therapy. Avenda Health. Accessed August 22, 2022. bit.ly/3pVhnVj

Avenda Health granted FDA breakthrough device designation for technology to treat prostate cancer. News release. Avenda Health. May 11, 2021. Accessed August 19, 2022. bwnews.pr/3caT95R

Priester A, Fan R, Shubert J, et al. A novel AI-derived metric identifies favorable candidates for focal therapy of prostate cancer and accurately predicts treatment margin efficacy. Presented at: Engineering and Urology Society 35th Annual Meeting; May 15, 2022; New Orleans, LA. Accessed August 19, 2022. bit.ly/3QS9ifX

Priester A, Fan R, Shubert J, et al. Defining prostate cancer focal therapy treatment margins with a machine learning model: improvement upon hemi-gland ablation. Presented at: Engineering and Urology Society 35th Annual Meeting; May 15, 2022; New Orleans, LA. Accessed August 19, 2022. bit.ly/3QS9ifX

Priester A, Shubert J, Bhatnagar, et al. Automatic ablation site selection for focal therapy. Presented at: Engineering and Urology Society 35th Annual Meeting; May 15, 2022; New Orleans, LA. Accessed August 19, 2022. bit.ly/3QS9ifX

Articles

For clinicians tasked with treating patients with prostate cancer, disease visualization has traditionally consisted of imprecise techniques such as MRI. However, a new artificial intelligence-based approach by Avenda Health is poised to potentially revolutionize the treatment landscape in the field.

AI-Powered Focal Therapy Maps Future Treatment Paradigm in Prostate Cancer

Research examining novel treatment options for patients with non–small cell lung cancer (NSCLC) actionable mutations has drastically expanded the treatment landscape for smaller subsets of patients. Soon that may include those with carcinoembryonic antigen–related cell adhesion molecule 5 (CEACAM5)-expressing tumors. The target has recently displayed great potential for investigators as a therapeutic target.

CEACAM5 is a cell surface glycoprotein that is not highly expressed in several normal tissues, including colon, esophagus, and head and neck. However, the protein is often highly expressed in a few tumor types, such as gastrointestinal, breast, and lung. Approximately 20% of patients with NSCLC exhibit overexpression of CEACAM5.

“[CEACAM5] is expressed primarily on adenocarcinomas but does have some expression in squamous tumors, as well,” Paul Bunn, MD, the James Dudley Chair in Cancer Research and a distinguished professor of medicine–medical oncology at the University of Colorado Anschutz Medical Campus in Aurora, said during an 

 scientific interchange and workshop. “This antigen is associated with tumor progression. It promotes cell proliferation and migration. It is expressed much more in lung tumors than in normal lung [tissue]. Therefore, it is amenable to development of antibody-drug conjugates [ADCs].”

Investigators have reported that high CEACAM5 expression may be associated with cell proliferation and migration.

 CEACAM5 can be detected using immunohistochemical (IHC) assays. Positive staining has been defined as any partial or complete tumor cell plasma membrane staining at a minimum of 2+ intensity.

 The definition is being used for patient selection and stratification in ongoing phase 2 and phase 3 clinical trials of the potential first-in-class CEACAM5-targeted agent tusamitamab ravtansine (formerly SAR408701).

Novel CEACAM5-Targeted Agent Displays Promising Early Regulst in NSCLC

Tusamitamab ravtansine is an ADC consisting of a humanized monoclonal antibody and a cytotoxic maytansinoid, DM4. The monoclonal antibody binds to CEACAM5 and the maytansinoid targets CEACAM5-expressing tumor cells. In preclinical studies, the agent was proven to selectively bind to CEACAM5 in human tissue and displayed cytotoxic activity, leading investigators to tab it as a promising candidate for the development as a treatment option for patients with CEACAM5positive tumors.

“This drug in preclinical models has had very good efficacy,” Bunn said. “Tumor reduction—not only tumor stasis, but actually reduction in tumor size—[was observed] in this in vivo animal model.”

Tusamitamab ravtansine is under investigation in patients with solid tumors in a phase 1/2 trial (NCT02187848). Eligible adult patients must have locally advanced/metastatic solid tumors that expressed or are likely to express CEACAM5 and have an ECOG performance status of 1 or less.

In the dose-escalation phase 1 portion of the trial, 31 patients received tusamitamab ravtansine at doses ranging from 5 to 150 mg/m

, given every 2 weeks intravenously (IV). The dose-limiting toxicity of reversible grade 3 microcystic keratopathy was reported in 3 of the 8 patients who received tusamitamab ravtansine 120 mg/m

 and in 2 of the 3 patients who were treated at 150 mg/m2. Investigators determined the maximum tolerated dose (MTD) of tusamitamab ravtansine to be 100 mg/m

As of January 2020, ninety-two patients were treated at the MTD in the nonsquamous NSCLC cohort of the trial. Twenty-eight of these patients were moderate expressors of CEACAM5 (IHC ≥ 2+ on 1%-50% of tumor cells) and 64 were high expressors (IHC ≥ 2+ on ≥ 50% of tumor cells). The median age of the treated patients was 62.5 years (range, 31-91) and the median number of prior lines of therapy for advanced disease was 3 (range, 1-10). Most patients were men (51.1%) and most had an ECOG performance status of 1 (71.7%).

Findings from the trial showed that the overall response rate (ORR) among moderate expressors was 7.1% (95% CI, 1.98%-22.65%), with all responses being confirmed partial responses (PRs). Additionally, 53.6% of patients experienced stable disease (SD), the disease control rate (DCR) was 60.7%, and 35.7% had progressive disease (PD). One patient in this subgroup was not evaluable (NE) at the time of the analysis.

Comparatively, patients in the high-expressor cohort achieved an ORR of 20.3% (95% CI, 12.27%-31.71%), with all responses being PRs again. Patients in this subgroup experienced SD at a rate of 43.8%, a DCR of 64.1%, and 32.8% had PD. Two patients were NE.

In the overall nonsquamous NSCLC cohort, the most common treatment-emergent adverse effects (TEAEs) were asthenia (38.0%), keratopathy/ keratitis (38.0%), peripheral neuropathy (26.1%), dyspnea (23.9%), and diarrhea (22.8%). Common hematologic toxicities included leukopenia (14.4%), thrombocytopenia (13.3%), and neutropenia (4.4%). Dose modifications due to TEAEs occurred in 33.7% of patients, 10.9% of which were associated with keratopathy/keratitis. Grade 3 or greater TEAEs were reported in a little less than half of patients (47.8%).

Corneal TEAEs leading to dose modification occurred in 27.2% of patients. Ten of these patients experienced at least 1 dose reduction and 1 patient was forced to discontinue treatment. The median time to recovery from this type of TEAE was 18.5 days (range, 2-82). “This keratitis is most likely due to the DM4,” Bunn said. “There are noninflammatory deposits at the cornea. Usually, it did not occur in the first couple cycles, but at cycle 4, this seemed to be manageable with dose delay and dose reduction. It does take a couple weeks for it to go away, so dose delay was very frequent. This is not something where prophylaxis works, but if [a patient] gets it, a treatment with topical steroids is recommended.”

Additional data from the phase 1/2 trial encompassing patients treated over a long term were presented at the 2022 American Society of Clinical Oncology Annual Meeting. In this analysis, the study authors focused on patients who had undergone treatment with tusamitamab ravtansine for at least 12 months as of December 2021.

Findings showed that 24 patients were treated for at least 6 months, 15 patients for at least 9 months, 11 patients for at least 12 months, 6 patients for at least 24 months, and 2 patients for at least 42 months (

 Five patients remained on treatment at the data cutoff, 1 of whom has remained on treatment for over 52 months. Among patients who were treated for at least a year, the median duration of treatment was 26.6 months (range, 12.1-45.3).

Patients in this cohort had a median age of 61 years (range, 41-91) and 81% had high CEACAM5 expression. The median number of prior regiments for advanced disease was 2 (range, 1-6), with 54.5% of patients having received prior anti–PD-1/PD-L1 therapy and 45.5% having received antitubulin therapy.

Of the patients who experienced a PR in the January 2020 analysis (n = 15), PR was still reported in 67% of patients who were treated for at least 6 months, 53% of patients who were treated for at least 9 months, and 47% of patients who were treated for at least a year. Additionally, patients who were treated for at least a year had better ECOG performance status and underwent fewer prior treatment regimens compared with the overall group. PR was also found to occur regardless of CEACAM5 expression level in patients who received tusamitamab ravtansine for at least a year.

In terms of safety, investigators noted that only 1 patient who was treated for at least 12 months was forced to discontinue treatment due to a TEAE, which was breast cancer. The most common TEAEs were corneal events; any-grade corneal TEAEs occurred in 73% of patients with 36% of these being grade 3 or greater. Treatment was delayed or the dose was reduced in 7 patients and no corneal TEAEs were deemed serious or led to treatment discontinuation.

Investigators concluded that heavily pretreated patients exhibited a durable and frequently sustained response to treatment with tusamitamab ravtansine. They also concluded that further clinical development of the agent is therefore warranted.

A Multitude of Tusamitamab Ravtansine Trials Are Now Underway

In response to the positive findings among patients with NSCLC and increased CEACAM5 expression who were treated with tusamitamab ravtansine, multiple clinical trials are actively recruiting to further examine the safety and efficacy of the agent. These include the phase 3 CARMEN-LC03 trial (NCT04154956), the phase 2 CARMEN-LC04 trial (NCT04394624), and the phase 2 CARMEN-LC05 trial (NCT04524689).

In CARMEN-LC03, approximately 554 patients with nonsquamous NSCLC and a CEACAM5 expression of at least 2+ in a minimum of 50% of tumor cells will be randomly assigned 1:1 to receive either tusamitamab ravtansine or the standard-of-care docetaxel. Patients in the tusamitamab ravtansine arm will receive the agent at a dose of 100 mg/m

 IV every 2 weeks and docetaxel will be given at a dose of 75 mg/m

The primary end points of the study are progression-free survival (PFS) by RECIST 1.1 criteria as assessed by an independent blinded review committee and overall survival. Secondary end points include ORR, duration of response, health-related quality of life, and safety.

CARMEN-LC04 will examine tusamitamab ravtansine in combination with monoclonal antibody ramucirumab (Cyramza) in approximately 36 pretreated patients with nonsquamous NSCLC with high CEACAM5 expression. Ramucirumab will be given IV prior to the IV administration of tusamitamab ravtansine every 2 weeks.

The primary outcome in the safety run-in (part 1) will be to assess the tolerability of the combination and confirm the recommended dose of tusamitamab ravtansine when it is given with ramucirumab. Part 2 will evaluate the antitumor activity of the combination, as well as safety, durability of response, PFS, pharmacokinetic profile, and immunogenicity.

Finally, CARMEN-LC05 will enroll approximately 96 patients with nonsquamous NSCLC with high CEACAM5 expression. Patients will be sorted into 1 of 4 experimental arms: (1) tusamitamab ravtansine plus pembrolizumab (Keytruda), (2) tusamitamab ravtansine plus pembrolizumab plus carboplatin, (3) tusamitamab ravtansine plus pembrolizumab plus cisplatin, or (4) tusamitamab ravtansine plus pembrolizumab plus carboplatin plus pemetrexed.

The primary objective of the trial is to assess each combination’s tolerability and to determine the recommended dose of tusamitamab ravtansine in each combination. Secondary objectives include evaluating the safety, antitumor activity, pharmacokinetics, and immunogenicity of each combination.

Gazzah A, Bedard PL, Hierro C, et al. Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody-drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study. 

. 2022;33(4):416-425. doi:10.1016/j.annonc.2021.12.012

Johnson ML, Chadjaa M, Yoruk S, Besse B. Phase III trial comparing antibody-drug conjugate (ADC) SAR408701 with docetaxel in patients with metastatic non-squamous non-small cell lung cancer (NSQ NSCLC) failing chemotherapy and immunotherapy. 

. 2020;38(suppl 15):TPS9625. doi:10.1200/JCO.2020.38.15_suppl. TPS9625

Decary S, Berne PF, Nicolazzi C, et al. Preclinical activity of SAR408701: a novel anti-CEACAM5-maytansinoid antibody-drug conjugate for the treatment of CEACAM5-positive epithelial tumors. 

. 2020;26(24):6589-6599. doi:10.1158/1078-0432. CCR-19-4051

LaPointe N, Hertle N, Hsu SC, et al. Validation of an immunohistochemical assay, CEACAM5 IHC 769, under development for use with the antibody-drug conjugate tusamitamab ravtansine (SAR408701). 

. 2021;39(suppl 15):e21030. doi:10.1200/ JCO.2021.39.15_suppl.e21030

Gazzah A, Ricordel C, Cousin S, et al. Efficacy and safety of the antibody-drug conjugate (ADC) SAR408701 in patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5). 

. 2020;38(suppl 15):9505. doi:10.1200/ JCO.2020.38.15_suppl.9505

Ricordel C, Barlesi F, Cousin S, et al. Safety and efficacy of tusamitamab ravtansine (SAR408701) in long-term treated patients with nonsquamous non-small cell lung cancer (NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5). 

. 2022;40(suppl 16):9039. doi:10.1200/ JCO.2022.40.16_suppl.9039

SAR408701 in combination with ramucirumab in pre-treated patients with non squamous non-small cell lung cancer (NSQ NSCLC) (CARMEN-LC04). ClinicalTrials.gov. Updated May 12, 2022. Accessed August 15, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04394624

Tusamitamab ravtansine (SAR408701) in combination with pembrolizumab and tusamitamab ravtansine (SAR408701) in combination with pembrolizumab and platinum-based chemotherapy with or without pemetrexed in patients with NSQ NSCLC (CARMEN-LC05) (CARMEN-LC05). ClinicalTrials.gov. Updated August 12, 2022. Accessed August 15, 2022. 

https://clinicaltrials.gov/ct2/show/ NCT04524689

Sponsored in part by Daiichi Sankyo. Content independently developed by

Paul Bunn, MD, elaborates on carcinoembryonic antigen–related cell adhesion molecule 5 as a potential target in the treatment of non–small cell lung cancer.

CEACAM5 Shows Great Potential as Therapeutic Target in NSCLC

For patients with myelofibrosis (MF), stem cell transplant continues to be the only curative treatment. Many patients, however, may not be eligible for transplants, including older adults or those whose disease is not yet deemed of high enough risk to warrant transplant. In these patients, medical treatments are crucial to control their symptoms and improve their overall quality of life.

In terms of myeloproliferative neoplasms, MF “is probably the most symptomatic disease, with a high burden on patients and worse outcome in general,” Rami Komrokji, MD, said during a recent 

. Komrokji served as moderator for a panel of hematology cancer experts who discussed the current treatment landscape and novel emerging therapies for patients with MF.

Three JAK inhibitors have been approved for patients with MF: ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo). Momelotinib is on track to become the fourth FDA-approved JAK inhibitor.

Ruxolitinib has been the standard of care for many patients with MF since 2011, when it became the first FDA-approved treatment for patients with MF. The initial approval was for patients with intermediate/high-risk primary or secondary MF based on data from the COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) trials.

 Both studies showed statistically significant reductions in spleen volume and improvement in total symptom scores (TSSs). “It was transformative because we had a treatment that improved patients’ quality of life and reduced spleen size,” Jamile Shammo, MD, said.

During the 2022 American Society of Clinical Oncology Annual Meeting (2022 ASCO) in June, a retrospective review of the medical records of 131 patients who received ruxolitinib for 3 or more years was presented.

 The study found that 40% of patients who remained on ruxolitinib for 3 or more years were alive 10 years after their treatment initiation. On multivariate analysis, age 65 years or older and neutropenia were predictive factors of survival.

“It’s a very good option for patients who have this disorder. We need to keep an eye on things like opportunistic infections—herpes zoster is 1 such issue—and cytopenias, which can be managed,” Shammo said.

Fedratinib became the second FDA-approved JAK inhibitor for patients with intermediate-2 or high-risk primary or secondary MF when it was finally approved in 2019 based on data from the JAKARTA (NCT01437787) and JAKARTA-2 (NCT01523171) studies.

 Its development had been slowed because it was placed on a clinical hold between 2013 and 2017.

“Approval of the drug was delayed because there was a very low rate of Wernicke encephalopathy [WE], probably interfering with thiamine metabolism to a small degree,” Ruben Mesa, MD, explained. WE had been observed in 1.3% of patients (8 of 608 study participants).

“There’s a black box warning that sounds scary but in practice is fairly simple. You check thiamine levels, and you replace thiamine, and thiamine is dirt cheap. I give patients a bottle. Then you monitor for Wernicke,” Mesa said.

Once it was determined that fedratinib does not directly induce WE and that the risk of the complication can be mitigated, the FDA approved it. Data from the JAKARTA studies showed statistically significant responses in spleen volume reduction (SVR) and MF symptoms.

 “If [patients] used ruxolitinib and still have [an enlarged] spleen and symptoms, and you don’t have a trial available, fedratinib is a good option. It can be used at full dose in patients with platelets between 50,000 and 100,000 per mm

Pacritinib received an accelerated approval from the FDA in February 2022 for adult patients with intermediate or high-risk primary or secondary MF based on data from the pivotal phase 3 PERSIST-2 (NCT02055781) study.

 PERSIST-2 randomly assigned 311 patients 1:1:1 to receive pacritinib 200 mg twice daily (n = 107), pacritinib 400 mg once daily (n = 104 patients), or best available therapy (BAT; n = 100), usually ruxolitinib (45% of patients). Prior JAK2 inhibitor therapy was permitted.

At week 24, the intention-to-treat efficacy population included 72 to 75 patients in each arm, and significantly more patients in the pacritinib arms vs BAT arm had SVR of 35% or greater (18% vs 3%, respectively; 

 = .001). Additionally, pacritinib- vs BAT-treated patients had a nonsignificantly higher rate of reduction in TSS of 50% or greater (25% vs 14%, respectively; 

 = .08). When comparing pacritinib dosing, pacritinib 200 mg twice daily was found to be the most efficacious, demonstrating significant reductions in both spleen volume and TSS vs BAT, with 22% vs 3% (

 = .001), respectively, experiencing SVR, and 32% vs 14% (

 = .01), respectively, experiencing reduction in TSS of 50% or greater.

Unlike ruxolitinib and fedratinib, pacritinib can be used irrespective of patients’ platelet counts and in the setting of marked thrombocytopenia. Mesa explained that this has been attributed to its inhibition of IRAK1. “It might be better for patients with cytopenic MF. In clinical studies, it could be used safely and effectively in individuals with platelet counts of less than 50,000 per mm

. It’s approved for individuals with marked thrombocytopenia in the front line and second line. It might also help to improve anemia,” he said, noting it is the first approved therapy that addresses the needs of patients with cytopenic MF, a group who previously had no treatment options.

Momelotinib, a highly selective JAK inhibitor, is being developed for patients with MF who are symptomatic and anemic. GSK has submitted a new drug application for momelotinib based on data from several studies, including the phase 3, randomized, double-blind MOMENTUM (NCT04173494) trial. The FDA is scheduled to make a decision by June 16, 2023.

“[Momelotinib is] a JAK1 and JAK2 inhibitor that we had noticed early on could help improve anemia. Just as we had learned early on that pacritinib may have less thrombocytopenia, momelotinib had something different. It might help to improve anemia and have less drug-emergent anemia,” Mesa said.

Momelotinib was first assessed in the phase 3 SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268) trials.

 In SIMPLIFY-1, 432 patients with either high-risk, intermediate-2 risk, or symptomatic intermediate-1 risk MF who had not received JAK inhibitor therapy were randomly assigned to 24 weeks of momelotinib 200 mg once daily or ruxolitinib 20 mg twice daily, after which all patients could receive open-label momelotinib.

 At 24 weeks, momelotinib was found to be noninferior to ruxolitinib for spleen response and inferior for symptom response, but momelotinib was associated with a reduced transfusion requirement.

“If we look at that analysis now, not inferior [for symptom response] probably would have been more accurate. But without question, it was better for anemia,” Mesa said. He explained that a multicenter analysis he participated in investigated the mechanism behind the improvement in anemia and discovered it was due to momelotinib’s suppression of hepcidin and inhibition of ACVR1.

SIMPLIFY-2 compared momelotinib with BAT in 156 patients with MF previously treated with ruxolitinib.

 At 24 weeks of treatment, 73 of 104 patients (70%) in the momelotinib arm and 40 of 52 patients (77%) in the BAT arm (ruxolitinib in 89% of patients) were still on treatment. Momelotinib was not superior to BAT in demonstrating a greater than 35% reduction in spleen size compared with baseline, with 7% vs 6% of patients, respectively, achieving this end point.

Because the data from SIMPLIFY-1 and SIMPLIFY-2 were muddy, the MOMENTUM trial was initiated to provide clarity. “We created the MOMENTUM study to have a very specific additional set of data that we thought were critical: second-line, symptomatic, and anemic patients who [did not have success with] ruxolitinib, and with a control arm that we think was arguably demonstrating that we don’t have a lot as it relates to anemia. But we do have danazol, an androgen,” Mesa said.

Data for the MOMENTUM trial were presented at 2022 ASCO (

 The trial compared momelotinib with danazol in 195 patients with MF previously treated with a JAK inhibitor who were symptomatic and anemic.

 Patients were randomly assigned 2:1 to receive momelotinib 200 mg once daily plus danazol placebo (n = 130) or danazol 600 mg once daily plus momelotinib placebo (n = 65) for 24 weeks, after which patients could receive open-label momelotinib. At 24 weeks, 72.3% of patients in the momelotinib arm and 58.5% of patients in the danazol arm completed treatment, with 70.8% and 55.4% of these patients, respectively, entering the momelotinib open-label extension.

Momelotinib was found to be superior to danazol in almost all end points assessed, including TSS response rate (24.6% vs 9.2%, respectively; 

 = .0095), SVR of at least 25% (40.0% vs 6.2%, respectively; 

 < .0001) and of at least 35% (23.1% vs 3.1%, respectively; 

 = .0006]), change in TSS from baseline (–9.36 vs –3.13, respectively; 

 = .0014), and zero transfusion rate (35.4% vs 16.9%, respectively; 

 = .0012). Momelotinib showed noninferiority to danazol in transfusion independence rate at 24 weeks (30.8% vs 20.0%, respectively; 

 = .0064). There was a trend toward improved overall survival (OS) with momelotinib vs danazol (HR, 0.506; 95% CI, 0.2381.076; 

Overall, momelotinib demonstrated a good safety profile. The most common treatment-related adverse effects (TRAEs) of grade 3 or greater severity included thrombocytopenia, which occurred in 22% of patients in the momelotinib arm and 12% of patients in the danazol arm; anemia, which occurred in 8% and 11% of these patients, respectively; and infections, which occurred in 15% and 17%, respectively. In all, TRAEs led to study discontinuation in 18% of momelotinib-treated patients and 23% of danazol-treated patients.

Similar findings were reported in a poster presented at 2022 ASCO that examined the safety and efficacy of momelotinib vs danazol among participants in MOMENTUM based on their baseline platelet counts.

 The assessment found that thrombocytopenic patients with platelet counts as low as 25 × 10

/L could be treated safely with momelotinib and showed improvements in symptom responses, splenic responses, and transfusion independence rates compared with danazol. As in the overall intention-to-treat population, platelet levels in thrombocytopenic patients were found to remain stable over time, and the trend toward improved OS was maintained.

“When we look at the experience of momelotinib in aggregate, it clearly paints a picture of a drug that would be very helpful to have in MF….It will have roles in some patients in the front line and clearly some patients in the second line. It will make a significant addition to the armamentarium if the drug is approved after all these data are reviewed by the FDA,” Mesa said.

In addition to JAK inhibitors, a variety of other novel agents with unique mechanisms of action are being tested in clinical trials as potential treatments for MF. The panelists indicated that some of these agents may lend themselves to promising combination approaches, particularly in combination with ruxolitinib, as well as provide patients with options after JAK2 inhibitor failure.

Navitoclax, a cousin of venetoclax (Venclexta), is an orally bioavailable small-molecule inhibitor of BCL2.

 pathway has been shown to overcome JAK inhibitor resistance in preclinical models.

 “For many reasons, it’s been speculated that the combination of trying to overcome apoptotic resistance and having JAK inhibition could be beneficial,” Mesa said.

Recently, data from the phase 2 REFINE trial (NCT03222609) were reported. The study assessed the addition of navitoclax to ruxolitinib for patients with MF and progression or suboptimal response while on a stable dose of ruxolitinib (≥ 10 mg twice daily).

 At week 24, the addition of navitoclax to ruxolitinib was found to result in durable SVR of 35% or greater and improvements in TSS, hemoglobin response, and change in bone marrow fibrosis grade. Two phase 3 trials exploring the potential of the combination of navitoclax and ruxolitinib to modify the course of the disease are underway: TRANSFORM-1 (NCT04472598) in patients who have not received JAK2 inhibitors and TRANSFORM-2 (NCT04468984) in patients whose disease has progressed or who have had a suboptimal response to ruxolitinib therapy. The comparison arms in the trials are ruxolitinib plus placebo and BAT, respectively.

Pelabresib is an investigational small molecule BET inhibitor that was assessed in the phase 1/2 MANIFEST trial (NCT02158858).

 In the study, pelabresib monotherapy showed signs of clinical activity in patients with advanced MF who were ineligible for JAK inhibitor therapy, including SVR, symptom improvement, and hemoglobin benefit.

Pelabresib is currently being assessed in the ongoing, global, phase 3, double-blind, randomized, placebo-controlled phase 3 MANIFEST-2 (NCT04603495) trial.

 MANIFEST-2 investigators are planning to enroll up to 400 patients with intermediate-1 or higher primary or secondary MF who have not been treated with a JAK inhibitor.

Patients will be treated with ruxolitinib twice daily on days 1 to 21 in 21-day cycles and randomly assigned 1:1 to receive concomitant pelabresib or concomitant placebo orally once daily on days 1 to 14 of treatment. The primary end point will be SVR of 35% or greater at 24 weeks, and the secondary end point will be reduction in TSS of 50% or greater from baseline at 24 weeks.

“BET inhibition does provide a novel mechanism of treating MF, which will hopefully help and boost not only the effectiveness of ruxolitinib, the duration of time that it’s working, but also perhaps have some type of effect on the natural history of the disease,” Jeanne M. Palmer, MD, said.

Imetelstat, a telomerase inhibitor, was evaluated in the phase 2, multicenter MYF2001 (NCT02426086) trial, which assessed 2 doses of imetelstat monotherapy in patients with relapsed or refractory intermediate-2 or high-risk MF previously treated with a JAK inhibitor.

 Patients were randomly assigned to receive either imetelstat 9.4 mg/kg or 4.7 mg/kg intravenously once every 3 weeks. Imetelstat 9.4 mg/kg showed clinical benefits. The median OS was 29.9 months among 59 patients who received the higher dose, with improvement in bone marrow fibrosis in 40.5% of 37 evaluable participants in that group. Additionally, 42.1% of patients treated with the higher dose had a reduction in the variant allele frequency of driver mutations, suggesting effects on the malignant clone.

“In the groups that have ruxolitinib failure, many studies have shown a survival in the range of a year and a half or less,” Komrokji said, indicating that the almost 30 months seen with imetelstat suggests an OS benefit.

Komrokji and colleagues came to this determination after comparing the findings in the MYF2001 trial with external real-world data that were collected from a study of 96 patients who had discontinued ruxolitinib and were subsequently treated with BAT at Moffitt Cancer Center in Tampa, Florida.

The real-world comparison showed BAT to have a 12-month OS in closely matched patients with MF after JAK inhibitor failure. Based on this OS signal, imetelstat is currently being assessed in the phase 3 MYF3001 trial (NCT04576156) comparing imetelstat with BAT in patients with intermediate-2 or high-risk MF who have not responded to JAK inhibitor treatment.

Mascarenhas J, Hoffman R. Ruxolitinib: the first FDA approved therapy for the treatment of myelofibrosis. 

. 2012;18(11):30083014. doi:10.1158/1078-0432.CCR-11-3145

Masarova L, Bose P, Pemmaraju N, et al. Characteristics of patients with myelofibrosis on ruxolitinib for three or more years. 

. 2022;40 (suppl 16):e19082. doi:10.1200/JCO.2022.40.16_suppl.e19082

Mullally A, Hood J, Harrison C, Mesa R. Fedratinib in myelofibrosis. 

. 2020;4(8):1792-1800. doi:10.1182/bloodadvances.2019000954

CTI BioPharma announces FDA accelerated approval of VONJO (pacritinib) for the treatment of adult patients with myelofibrosis and thrombocytopenia. News release. CTI BioPharma Corp. February 28, 2022. Accessed August 14, 2022. https://bit.ly/3K0e743

Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. 

. 2018;4(5):652-659. doi:10.1001/jamaoncol.2017.5818

US FDA accepts new drug application for GSK’s momelotinib for the treatment of myelofibrosis. News release. GSK plc. August 17, 2022. Accessed August 19, 2022. https://bit.ly/3Ck8R9A

Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naïve patients with myelofibrosis. 

. 2017;35(34):3844-3850. doi:10.1200/JCO.2017.73.4418

Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. 

. 2018;5(2):e73-e81. doi:10.1016/S2352-3026(17)30237-5

Mesa RA, Gerds AT, Vannucchi A, et al. MOMENTUM: phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. 

. 2022;40(suppl 16):7002. doi:10.1200/JCO.2022.40.16_suppl.7002

Gerds AT, Verstovsek S, Vannucchi A, et al. Thrombocytopenic myelofibrosis patients previously treated with a JAK inhibitor in a phase 3 randomized study of momelotinib versus danazol [MOMENTUM]. 

. 2022;40(suppl 16):7061. doi:10.1200/JCO.2022.40.16_suppl.7061

Harrison CN, Garcia JS, Somervaille TCP, et al. Addition of navitoclax to ongoing ruxolitinib therapy for patients with myelofibrosis with progression or suboptimal response: phase II safety and efficacy. 

. 2022;40(15):1671-1680. doi:10.1200/JCO.21.02188

Kremyanskaya, M, Mascarenhas J, Palandri F, et al. Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis – update of clinical and translational data from the ongoing manifest trial. 

. 2021;138(suppl 1):141-144. doi:10.1182/blood-2021-150172

Harrison CN, Gupta VK, Gerds AT, et al. Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis. 

. Published online August 11, 2022. doi:10.2217/fon-2022-0484

Mascarenhas J, Komrokji RS, Palandri F, et al. Randomized, single-blind, multicenter phase II study of two doses of imetelstat in relapsed or refractory myelofibrosis. 

. 2021;39(26):2881-2892. doi:10.1200/JCO.20.02864

Kuykendall AT, Sun L, Mascarenhas J, et al. Favorable overall survival with imetelstat in relapsed/refractory myelofibrosis patients compared with real-world data. 

. 2022;101(1):139-146. doi:10.1007/s00277-021-04683-w

A study comparing imetelstat versus best available therapy for the treatment of intermediate-2 or high-risk myelofibrosis (MF) who have not responded to Janus kinase (JAK)-inhibitor treatment. ClinicalTrials.gov. Updated July 27, 2022. Accessed August 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04576156

A panel of hematology cancer experts discuss the current treatment landscape and novel emerging therapies for patients with myelofibrosis.

New JAK Inhibitors and Emerging Novel Agents Expand Myelofibrosis Treatment Arsenal

DNA damage homologous recombination repair (HRR) genotypic variants are not created equal. Patients with metastatic castration-resistant prostate cancer (mCRPC), whose disease harbors somatic mutations, including 

, have demonstrated response to PARP inhibitors such as olaparib (Lynparza) and rucaparib (Rubraca). However, for the approximately 5% of patients with CDK12 variants, outcomes have been limited.

Descriptive analyses have detailed the unique genomic profiles of tumors with CDK12 mutations.

 For example, in an analysis of 4918 mCRPC tumors, 6.4% of samples were positive for 

 mutations. When investigators explored the genomic profiles of these tumors and compared them with the tumors of patients without 

 wild-type disease, differences were present. Among patients with 

 mutations, there were significantly fewer loss-of-function genomic alterations in 

Investigators noted that the lower frequencies of these genomic alterations were associated with homologous recombination defect and the mTOR pathway, signaling that platinum agents, PARP inhibitors, and PIK3CA, AKT, or mTOR inhibitors may have efficacy for these patients.

 (P < .001) were reported among patients with 

 mutations in addition to higher frequency of cell regulatory genes 

 (P = .002). Finally, investigators also observed that microsatellite instability–high status was more frequent in patients with 

 mutationpositive disease vs those without (6% vs 3%; P = .007). The median tumor mutational burden was the same between the cohorts at 2.5.

DNA damage homologous recombination repair genotypic variants are not created equal. 

Vol. 23/No. 17 | Oncology Live®

AI-Powered Focal Therapy Maps Future Treatment Paradigm in Prostate Cancer

CEACAM5 Shows Great Potential as Therapeutic Target in NSCLC

New JAK Inhibitors and Emerging Novel Agents Expand Myelofibrosis Treatment Arsenal

Investigative Approaches Seek to Enhance Outcomes for Patients With CDK12-Mutant mCRPC

Metastatic Breast Cancer Enters a New Era of HER2 Classification